The prevalence of nicotine dependence, its accompanying health problems, and the difficulty users have in maintaining abstinence combine to make tobacco dependence a major public health challenge for society. Clinical studies were designed to provide a better understanding of the pathophysiology and mechanisms of nicotine dependence as well as to contribute to the development of putative new smoking cessation treatments. Several nicotine delivery systems have been developed to aid in smoking cessation. Two of these, nicotine polacrilex and nicotine transdermal patches, have been approved for over the counter sales for this purpose. Other nicotine delivery systems developed for smoking cessation indications, include a nicotine nasal spray and a nicotine vapor inhaler. These systems are notable for having a more rapid delivery rate, a factor that has been associated with greater potential for abuse. Therefore, although developed as aids for smoking cessation, such systems may be abused in their own right. The pharmacodynamic and pharmacokinetic effects of a new treatment for tobacco withdrawal were studied in an outpatient protocol. We found that treating cigarettes with a corn syrup-based solution significantly reduced exposure to nicotine and CO. Further, the effects were similar in men and women. Pharmacokinetic effects of nicotine were similar in men and women indicating that gender differences in patterns of smoking and tobacco withdrawal are not due to gender differences in nicotine metabolism. The effects of befloxatone, a reversible MAO-A inhibitor were evaluated for smoking cessation therapy in a multicenter clinical trial. A preliminary evaluation of cigarettes was conducted. In another study, denicotinized cigarettes were used in a rapid smoking protocol and as a control condition in an experiment to test the influence of cues on smoking behavior. In a recent evaluation of smoking among US teenagers, we have identified risk and protective factors that predispose or prevent the initiation of cigarette smoking. More recently influence of cigarette smoking on co-incident marijuana smoking among US teens was evaluated.